Sofia Beloka

Beta-adrenergic blockade and metabo-chemoreflex contributions to exercise capacity.

PURPOSE Exercise-induced dyspnea in patients with cardiopulmonary diseases may be related to sympathetic nervous system activation, with increased metabo- and/or chemosensitivities. Whether this mechanism plays a role in exercising normal subjects remains unclear. METHODS Muscle sympathetic nerve activity (MSNA), HR, ventilation (V(E)), O2 saturation (SpO2), and end-tidal PCO2 (PetCO2) were measured in 14 healthy young adults after 1 wk of beta1-receptor blockade with bisoprolol 5 mg x d(-1) versus placebo after a double-blind, placebo-controlled, randomized crossover design. The MSNA and the ventilatory responses to hyperoxic hypercapnia (7% CO2 in O2), DeltaV(E)/DeltaPetCO2, and isocapnic hypoxia (10% O2 in N2), DeltaV(E)/DeltaSpO2, and to an isometric muscle contraction followed by a local circulatory arrest (metaboreflex) were determined at rest followed by an incremental cardiopulmonary exercise test. RESULTS Bisoprolol did not change the V(E) and MSNA responses to hypercapnia, hyperoxia, or isometric muscle contraction or ischemia. Bisoprolol decreased maximum O2 uptake (P < 0.05), workload (P < 0.05), and HR (P < 0.0001) and both V(E)/VO2 and V(E)/VCO2 slopes (P < 0.05). CONCLUSIONS These results suggest that decreased aerobic exercise capacity after intake of beta-blockers is accompanied by decreased ventilation at any metabolic rate. However, this occurs without detectable change in the sympathetic nervous system tone or in metabo- or chemosensitivity and is therefore probably of hemodynamic origin.

Differential effects of metaboreceptor and chemoreceptor activation on sympathetic and cardiac baroreflex control following exercise in hypoxia in human.

Muscle metaboreceptors and peripheral chemoreceptors exert differential effects on the cardiorespiratory and autonomic responses following hypoxic exercise. Whether these effects are accompanied by specific changes in sympathetic and cardiac baroreflex control is not known. Sympathetic and cardiac baroreflex functions were assessed by intravenous nitroprusside and phenylephrine boluses in 15 young male subjects. Recordings were performed in random order, under locally circulatory arrested conditions, during: (1) rest and normoxia (no metaboreflex and no chemoreflex activation); (2) normoxic post‐handgrip exercise at 30% of maximum voluntary contraction (metaboreflex activation without chemoreflex activation); (3) hypoxia without handgrip (10% O2 in N2, chemoreflex activation without metaboreflex activation); and (4) post‐handgrip exercise in hypoxia (chemoreflex and metaboreflex activation). When compared with normoxic rest (−42 ± 7% muscle sympathetic nerve activity (MSNA) mmHg−1), sympathetic baroreflex sensitivity did not change during normoxic post‐exercise ischaemia (PEI; −53 ± 9% MSNA mmHg−1, P= 0.5) and increased during resting hypoxia (−68 ± 5% MSNA mmHg−1, P < 0.01). Sympathetic baroreflex sensitivity decreased during PEI in hypoxia (−35 ± 6% MSNA mmHg−1, P < 0.001 versus hypoxia without exercise; P= 0.16 versus normoxic PEI). Conversely, when compared with normoxic rest (11.1 ± 1.7 ms mmHg−1), cardiac baroreflex sensitivity did not change during normoxic PEI (8.3 ± 1.3 ms mmHg−1, P= 0.09), but decreased during resting hypoxia (7.3 ± 0.8 ms mmHg−1, P < 0.05). Cardiac baroreflex sensitivity was lowest during PEI in hypoxia (4.3 ± 1 ms mmHg−1, P < 0.01 versus hypoxia without exercise; P < 0.001 versus normoxic exercise). The metaboreceptors and chemoreceptors exert differential effects on sympathetic and cardiac baroreflex function. Metaboreceptor activation is the major determinant of sympathetic baroreflex sensitivity, when these receptors are stimulated in the presence of hypoxia.

Nicotine increases chemoreflex sensitivity to hypoxia in non-smokers.

Background The peripheral chemoreflex contributes to cardiovascular regulation and represents the first line of defence against hypoxia. The effects of nicotine on chemoreflex regulation in non-smoking humans are unknown. Method We conducted a prospective, randomized, crossover, and placebo-controlled study in 20 male non-smokers to test the hypothesis that nicotine increases chemoreflex sensitivity. The effects of two intakes of 2 mg nicotine tabs and placebo on sympathetic nerve activity to muscle circulation (muscle sympathetic nerve activity; MSNA), minute ventilation (Ve), blood pressure and heart rate were assessed during normoxia, moderate isocapnic hypoxia, hyperoxic hypercapnia and an isometric handgrip in 10 subjects. Maximal end-expiratory apnoeas were performed at baseline and at the end of the fifth minute of hypoxia. In a second experimental setting, we studied the ventilatory response to a more marked isocapnic hypoxia in 10 other volunteers. Results Mean MSNA and Ve were not modified by nicotine during the 5 min of normoxia or moderate hypoxia. In the presence of nicotine MSNA was related to oxygen desaturation (P < 0.01). The sympathoexcitatory effects of nicotine became especially evident when apnoeas achieved oxygen saturations less than 85% (511 ± 44% increase in MSNA after the first intake, and 436 ± 43% increase after the second intake versus 387 ± 56% and 338 ± 31% with placebo, respectively, P < 0.05). Nicotine also increased the ventilatory response compared with placebo when oxygen saturation decreased to less than 85% (P < 0.05). Conclusion This is the first study to demonstrate that nicotine increases peripheral chemoreflex sensitivity to large reductions in arterial oxygen content in healthy non-smokers.

Intensified Large Artery and Microvascular Response to Cold Adrenergic Stimulation in African Blacks

BACKGROUND Arterial stiffening is more accelerated in blacks than in whites. Whether this is attributed to an enhanced vascular reactivity to environmental stress stimulation remains unknown. We therefore decided to test the hypothesis that cold pressor test (CPT) elicits a greater increase in arterial stiffness and an enhanced sympathetic skin vasoconstriction in African blacks than in whites normotensives. METHODS A total of 17 young normotensive African blacks and 17 normotensive whites were recruited. All underwent continuous assessment of blood pressure (BP), heart rate, and carotid-femoral pulse wave velocity (PWVc-f) at rest, during and after hand immersion in iced water (CPT). Concomitantly, skin microvascular blood flow was monitored by laser Doppler flowmetry on the opposite hand. RESULTS At baseline, African blacks exhibited higher values of PWVc-f than whites (7.2 +/- 0.3 vs. 6.5 +/- 0.2 m/s, respectively, P = 0.04). During CPT the increases in systolic BP and PWVc-f were greater in African blacks than in whites (systolic BP 17 +/- 2 mm Hg vs. 9 +/- 3 mm Hg, P < 0.001 and PWVc-f 0.62 +/- 0.1 m/s vs. 0.26 +/- 0.1 m/s, P = 0.03, respectively). However, there was no significant difference in the PWVc-f responses among the groups during CPT after adjustment for the increments in mean BP. Finally, CPT induced a more pronounced skin microvascular vasoconstriction in African blacks than in whites (-54.4 +/- 5 % vs. -31.3 +/- 6 %, P < 0.001). CONCLUSIONS CPT provokes a more pronounced increase in PWVc-f in normotensive African blacks than in whites, that appears to be due to a greater increase in mean BP. Additionally, African blacks present an intensified skin microvascular response to the CPT as compared to their whites counterparts.

Decreased ventilatory response to exercise by dopamine-induced inhibition of peripheral chemosensitivity.

The contribution of the peripheral chemoreflex to the ventilatory response to exercise and aerobic exercise capacity remains incompletely understood. Low-dose dopamine has been reported to specifically inhibit the peripheral chemoreceptors. We therefore investigated the effects of intravenous dopamine (3 microg kg(-1)min(-1)) on cardiopulmonary exercise test (CPET) variables in 13 healthy young male subjects. The study was prospective, placebo-controlled, and randomized with more than 24h between placebo and dopamine administrations. During the CPET, dopamine decreased the .V(E)/.V(CO2) output slope (24.61+/-1.84 vs. 23.09+/-1.81, placebo vs. Dopamine respectively, p=0.025), without affecting maximum workload, .V(E) and O(2) uptake. In conclusion, our study reveals that inhibition of peripheral chemoreflex function with dopamine decreases the .V(E)/.V(CO2) slope during dynamic exercise, with no change in aerobic exercise capacity.

BRS analysis from baroreflex sequences and baroreflex events compared using spontaneous and drug induced data

Spontaneous time domain BRS estimation is based on the SBP-RR slope, which can be computed from either baroreflex sequences (BS) or baroreflex events (BE). BRS analysis from BEs was recently shown be advantageous particularly in the cases of reduced BRS or when BS are not identified. Also, it offers a superior discrimination between lying and standing positions. In this work, the methods developed for spontaneous BRS analysis are further compared using spontaneous and drug induced data. The results corroborate that spontaneous and drug induced estimates are different although correlated. In particular, if BEs are used the differences and the correlation between the estimates is higher. No precision improvement is achieved if the BRS is estimated from drug induced data. In spontaneous, the higher number of beats in BEs in comparison with BSs (at the expense of a lower SBP-RR correlation) allows a higher BRS estimate precision using recordings of the same length.

Differential Effects of Oral β Blockade on Cardiovascular and Sympathetic Regulation

In patients with hypertension, β blockade decreases muscle sympathetic nerve activity (MSNA; micrographic technique) expressed in burst frequency (burst/min) but does not affect MSNA expressed in burst incidence (burst/100 heart beats), because reductions in blood pressure (BP) upon each diastole continue to deactivate the arterial baroreceptors, but at a slower heart rate (HR). We studied the effects of oral β blockade on MSNA and baroreflex sensitivity (BRS) in normal participants. Bisoprolol (5 mg, 1 week) was administered in 10 healthy young adults, using a double-blind, placebo-controlled, randomized cross-over study design. The beat-to-beat mean RR interval (RR) and systolic blood pressure (SBP) series were analyzed by power spectral analysis and power computation over the very low frequency (VLF), low frequency, and high frequency (HF) bands. Baroreflex sensitivity was computed from SBP and RR cross-analysis, using time and frequency domain methods. Bisoprolol increased RR (P < .0005), decreased mean SBP and diastolic blood pressure values (P < .01), did not change the SBP and RR powers, except for RR power in VLF (P < .02) and SBP power in HF (P < .03). The MSNA variability (P > .13) and respiratory pattern (P = .84) did not change from placebo to bisoprolol condition. The bisoprolol-induced bradycardia was associated with higher burst/100 heart beats (P < .05) and bisoprolol did not affect burst/min (P = .80). Time domain BRS estimates were increased after bisoprolol (P < .05), while frequency domain ones did not change (P > .1). Oral bisoprolol induces differential effects on sympathetic burst frequency and incidence in normal participants. Peripheral sympathetic outflow over time is preserved as a result of an increased burst incidence, in the presence of a slower HR. Unchanged BP and HR and MSNA variability suggests that the larger burst incidence is not due to sympathetic activation.

Digoxin increases peripheral chemosensitivity and the ventilatory response to exercise in normal subjects.

1. The contribution of peripheral chemoreceptors to the regulation of ventilation during exercise remains incompletely understood. Digoxin has been reported to increase chemoreflex sensitivity in humans. In the present randomized, cross‐over, double‐blind study, we tested the hypothesis that this increases the ventilatory response to exercise in normal subjects, as assessed by changes in minute ventilation (VE) in response to the rate of CO2 production (Vco2).

Effects of digoxin on muscle reflexes in normal humans.

Blockade of the skeletal muscle Na+–K+-ATPase pump by digoxin could result in a more marked hyperkaliema during a forearm exercise, which in turn could stimulate the mechano- and metaboreceptors. In a randomized, double-blinded, placebo-controlled, and cross-over-design study, we measured mean blood pressure (MBP), heart rate (HR), ventilation (VE), oxygen saturation (SpO2), muscle sympathetic nerve activity (MSNA), venous plasma potassium and lactic acid during dynamic handgrip exercises, and local circulatory arrest in 11 healthy subjects. Digoxin enhanced MBP during exercise but not during the post-handgrip ischemia and had no effect on HR, VE, SpO2, and MSNA. Venous plasma potassium and lactic acid were also not affected by digoxin-induced skeletal muscle Na+–K+-ATPase blockade. We conclude that digoxin increased MBP during dynamic exercise in healthy humans, independently of changes in potassium and lactic acid. A modest direct sensitization of the muscle mechanoreceptors is unlikely and other mechanisms, independent of muscle reflexes and related to the inotropic effects of digoxin, might be implicated.

ENDOTHELIN CONTRIBUTES TO THE RISE IN BLOOD PRESSURE IN RESPONSE TO HYPOXIA IN PATIENTS WITH SEVERE OBSTRUCTIVE SLEEP APNEAS: PP.32.272

Background: Obstructive sleep apnea (OSA) is strongly correlated with an increased risk of systemic hypertension. However, the link between systemic hypertension and nocturnal apneas remains incompletely understood. Animal studies suggest an implication of the endothelin system. The aim of the study is to determine if endogenous endothelin (ET) plays a role in the increase in blood pressure observed during hypoxic episodes in OSA patients, in addition to peripheral chemoreflex and sympathetic nerve activation. Methods: We assessed the effects of the nonspecific ET antagonist bosentan (500 mg; Tracleer; Actelion; Basel, Switzerland) on ventilation, hemodynamics, and muscle sympathetic nerve activity (MSNA) during normoxia and isocapnic hypoxia using a randomized, crossover, double-blinded, placebo-controlled study design, in 13 severely untreated sleep apneic patients (age 50 ± 9 years, apnea-hypopnea index 44 ± 19 per hour). Results: Hypoxia increased blood pressure, MSNA and minute ventilation as oxygen saturation decreased. Bosentan suppressed completely the increase in systolic blood pressure during a 5 minute hypoxic challenge (143 ± 5 mmHg during hypoxia vs. 133 ± 5 mmHg during normoxia with placebo; 127 ± 3 mmHg during hypoxia vs. 125 ± 3 mmHg during normoxia under bosentan, p = 0.023). Diastolic blood pressure, and the rise in MSNA and ventilation during isocapnic hypoxia did not differ between bosentan and placebo. Conclusion: ET contributes to the rise in systolic pressure in response to acute hypoxia in patients with severely untreated OSA. This was not due to lower chemoreflex activation with bosentan.